Reaction mass of cerium phosphate and lanthanum phosphate and terbium phosphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles (as the data is used in a read-across approach, a maximal reliability score of 2 was attributed).

Data source

Reference

Reference Type:

publication

Title:

Systemic lanthanum is excreted in the bile of rats

Author:

Damment S.J.P. and Pennick M.

Year:

2007

Bibliographic source:

Toxicology Letters 171: 69-77

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Lanthanum chloride was administered by intravenous injection to rats and the plasma lanthanum concentration as well as the excretion in faeces and urine were determined (three independent experiments).
Experiment 1: Male and female rats (N = 18 weight range 140 -192 g) received a single i.v. dose of 0.03 mg/kg of lanthanum chloride and lanthanum plasma levels were monitored at regular intervals up to 24 h after adminstration of the test substance.
Experiment 2: Male rats (N= 21 weight range 243 to 265 g) received a single i.v. dose of 0.3 mg/kg of lanthanum chloride and lanthanum plasma levels were determined at regular intervals up to 72 h post dose.
Experiment 3: Male rats (N = 12, weight range 189 to 207 g) received a single i.v. dose of either 0.3 mg/kg lanthanum chloride or saline. Urine and faeces samples were collected up to day 42 post dose.
Experiment 4: Male bile cannulated rats (N= 6 weight range 191 to 255 g) received 0.3 mg/kg of lanthanum chloride i.v. 24 h after the cannulation surgery. Bile, faeces and urine were collected at 24 h intervals for up to 5 days.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Lanthanum chloride, anhydrous

EC Number:

233-237-5

EC Name:

Lanthanum chloride, anhydrous

Cas Number:

10099-58-8

Molecular formula:

Cl3La

IUPAC Name:

lanthanum trichloride

Details on test material:

- Name of test material (as cited in study report): Lanthanum chloride
- Analytical purity: no data

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd. (Margate, UK) or Harlan UK Ltd. (Bicester, UK).
- Weight at study initiation:
Experiment 1: 140-192 g
Experiment 2: 243 - 265 g (males only)
Experiment 3: 198 - 207 g (males only)
Experiment 4: 191 - 255 g (males only)

Administration / exposure

Route of administration:

intravenous

Vehicle:

other: sodium chloride 0.9% w/vsolution

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Lanthanum chloride was formulated in sterile 0.9% (w/v) sodium chloride.

Duration and frequency of treatment / exposure:

single dose
Experiment 1: 24 h study duration
Experiment 2: 72 h study duration
Experiment 3: 42 days study duration
Experiment 5: 5 days study duration

Doses / concentrations

Remarks:

Doses / Concentrations:
Experiment 1: 0.03 mg/kg lanthanum chloride (0.017 mg/kg elemental lanthanum)
Experiment 2, 3 and 4: 0.3 mg/kg lanthanum chloride (0.17 mg/kg elemental lanthanum)

No. of animals per sex per dose / concentration:

Experiment 1: two or three animals per sex, per time point (total number: n = 18)
Experiment 2: total number: n = 21 (only males)
Experiment 3: total number 12, 6 treated, 6 control (only males)
Experiment 4: total number 6 (only males)

Control animals:

yes, concurrent vehicle

Details on study design:

Experiment 3: After injection rats were housed individually in metabolism cages to allow separate collection of 24 h urine and faeces samples.
Experiment 4: The bile duct was surgically cannulated in a similar group of male rats prior to drug administration. Rats were anaesthetized with isoflurane and a flexible plastic cannula inserted into the common bile duct. The cannula was exteriorized to allow free movement and complete bile collection. After a recovery period of 24 h, rats received a single dose of 0.3 mg/kg lanthanum chloride (0.17 mg/kg elemental lanthanum) by intravenous injection and were housed individually in metabolism cages for the separate collection of bile, faeces and urine at 24-h intervals for a period of 5
days.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (distribution, excretion after i.v. dosing, AUC determination
Eperiment 1 and 2
- Tissues and body fluids sampled: blood, plasma
- Time and frequency of plasma sampling: Experiment 1: pre-dose, 15 min., 1, 2, 4, 8 and 24 h after administration; Experiment 2: pre-dose, 5, 10, 20 and 40 min., 1, 2, 4, 8, 12, 18, 24, 48, 72 h

Sample PREPARATION and analysis Plasma Experiment 1 and 2
- Blood was centrifuged and plasma separated and diluted with tetramethyl ammonium hydroxide (TMAH) solution (1.25% [w/v] containing 0.1% [w/v] ethylenediaminetetraacetic acid diammonium salt [EDTA (NH4)2] as a lanthanum chelator). Lanthanum content was determined using an Agilent (Hewlett Packard) 4500 inductively coupled plasma (ICP)-mass spectrometer fitted with a Babington V-groove nebulizer and a glass spray chamber.
- The lower limit of quantification was 0.05 ng/mL.

Experiment 3 and 4
Experiment 3: Excreta samples were collected for the first 14 days, and then on days 21, 28, 35 and 42 post-dose.
Experiment 4: Bile, faeces and urine were collected at 24-h intervals for a period of 5 days.

Urine and bile samples were diluted in TMAH (tetramethyl ammonium hydroxide) solution; Lanthanum content was determined using an Agilent (Hewlett Packard) 4500 inductively coupled plasma (ICP)-mass spectrometer fitted with a Babington V-groove nebulizer and a glass spray chamber (Scott double pass cooled to 2°C). The lower limit of quantification was 0.05 ng/mL.
Faecal samples were quantitatively homogenized with distilled water, dried overnight at 105 ± 2 °C, acid-digested by heating with 2.0 mL nitric acid and 0.5 mL perchloric acid, and quantitatively resuspended in 1% nitric acid. Lanthanum content was determined using an Agilent 4500 ICP-mass spectrometer (lower limit of lanthanum quantification: 0.4 ng/mL).

Statistics:

Pharmacokinetic parameters were derived from plasma lanthanum concentrations by visual inspection of the individual or mean plasma concentration curves or by non-compartmental analysis using WinNonlin® (Version 3.0, Pharsight Corporation, Mountain View, California).
The observed maximum plasma lanthanum concentration (Cmax) and the time post-dose at which Cmax occurred (Tmax) were determined by visual inspection of individual or mean plasma concentration versus time curves. The area under the plasma concentration versus time curves, calculated from time 0 to 24 h post-dose (AUC 0–24), and from time 0 to the last sample collection time (AUC last) were calculated using linear trapezoidal summation from time 0 to the appropriate time point. Total clearance (CL) following intravenous administration was calculated as Dose IV/AUC IV, and volume of distribution (Vz) was calculated as CL/k, where k was the terminal rate constant calculated following log-linear regression analysis of the linear phase of the concentration–time profile.

Results and discussion

Preliminary studies:

no data

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not appliable as this summary concerns only the i.v. part of the publication

Details on distribution in tissues:

Experiment 2:
Following intravenous injection of 0.3 mg/kg lanthanum chloride (the maximum tolerated intravenous dose established in previous studies), plasma lanthanum levels decreased rapidly from a peak of 3231±233 ng/mL measured at 5 min, to approximately 14% of Cmax by 2 h postdose. Thereafter, plasma concentrations declined at a slower rate and returned to pre-dose concentrations (3.08 ± 2.91 ng/mL) by 48 h.
The systemic clearance of lanthanum was relatively low: 0.66 mL/(min. kg) compared with a reported cardiac output of 160 mL/(min kg) and a hepatic plasma flow of 30 mL/(min kg) for male rats as reported in the literature. Combined with a Vz (volume of distribution) of 1.30 L/kg that exceeded total body water (0.7 L/kg), it can be suggested that lanthanum was distributed into tissues, from where it was eliminated at a slower rate. The whole blood to plasma lanthanum ratio based on AUC last was calculated as 0.55, indicating that very little lanthanum entered or was bound to red blood cells. In vitro plasma binding studies reported in the same paper showed a plasma protein binding of lanthanum of > 99.7% in both rat and human plasma.

Details on excretion:

Experiment 3: After a single i.v. dose of 0.3 mg/kg of lanthanum chloride 76.4 +- 5.69% of lanthanum was recovered over 42 days. 96.9 +- 0.5% of this dose was excreted in the faeces, most of it (87.7 +- 3.81%) in the first 14 days. Only 0.63 +- 0.45% was recovered in the faeces between day 35 and 42 after dosing. Only 1.94 +- 0.24% of the administered La was excreted in the urine within 42 d; 41.0 +- 1.98% of this amount was excreted in the urine in the first 24 h after dosing. The amounts of excreted La were corrected for background values of La excreted by control rats. The lanthanum content of the faeces of control rats was up to 40.5 +- 1.92 micro-g over 42 days (this would hav been equivalent to 48% of the dose in treated animals). The concentration of La in the urine of untreated controls was below the limit of quantification of 0.4 ng/mL. The relatively low total recovery is attributed in part by the authors to the underestimation of fecal excretion due to the high background levels in faeces. Another reason may be a tissue distribution e.g. into bone tissue at the high i.v. dose that were associated with non-linar pharmacokinetics and are suggestive of a saturation of plasma binding and/or clearance mechanisms. An internal dose of 40 micro-g of La for a 250 g rat may have exceeded a calculated plasma binding capacity of 15 micro-g of La per 50 g rat as stated by the authors.
Experiment 4:
In bile duct cannulated rats receiving an i.v. dose of 0.3 mg/kg bw the recovery was very low. Only 12 +- 3.29% of the administered dose was recovered over the 5 day collection period. Of the recovered amoutn 85.6 +- 2.97% was excreted in the bile, 5.96 +- 3.41% was found in the faeces and 5.74 +- 0.91% in urine. The reduced recovery in bile cannulated rats is attributed by the authors to the bile cannulation surgery and/or the anaesthesia that could have caused a transient fall in bile flow.

Following intravenous administration of lanthanum chloride, biliary excretion was the predominant route of elimination, with 85.6% of recovered lanthanum collected from bile over a period of 5 days. However, a significant proportion (5.96%) of the element was recovered in the faeces of bile-duct cannulated animals, suggesting that lanthanum may also be eliminated directly across the gut wall.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#2

Toxicokinetic parameters:

Tmax: 5 min

Toxicokinetic parameters 2

Test no.:

#2

Toxicokinetic parameters:

Cmax: 3231+/-233 ng/mL

Toxicokinetic parameters 3

Test no.:

#2

Toxicokinetic parameters:

C(time): 48 h: 3.08 +/- 2.91 ng/mL

Toxicokinetic parameters 4

Test no.:

#1

Toxicokinetic parameters:

AUC: 45.07 ng*h/mL

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

For inorganic compounds metabolism is not relevant

Any other information on results incl. tables

Experiment 2:

After i.v. administration of 0.3 mg/kg lanthanum chloride a peak plasma concentration was reached 5 min after administration with 3231 +/- 233 ng/mL. This declined to approximately 14% of the value within 2 h. Thereafter plasma concentrations declined at a slower rate. They returned to pre-dose levels (3.08 +/- 2.91 ng/mL) after 48 h.

Experiment 1:

The i.v. AUC was calculated after administration of a lower dose of lanthanum chloride of 0.03 mg/kg equivalent to 0.017 mgLa/kg. The AUC(0 -24 h) was 45.07 ng h/mL.

Experiment 3:

Excretion of La after a single i.v. administration of 0.5 mg/kg lanthanum chloride within 42 days:

% of administered dose (mean +/- standard error of mean (S.E.M)), N = 6

Faeces: 74.1 +/- 5.82

Urine: 1.94 +/- 0.24

Cage wash: 0.31 +/- 0.04

Total: 76.4 +/- 5.69

% of recovered dose (mean +/- S.E.M.), N = 6

Faeces: 96.9 +/- 0.50

Urine: 2.66 +/- 0.49

Cage wash: 0.41 +/- 0.05

Total: 100

Experiment 4:

Recovery of lanthanum 5 days after administration of a single i.v. dose of 0.3 mg/kg lanthanum chloride

% of administered dose (mean +/- S.E.M.) N = 6

Bile: 10.0 +/- 2.46

Feaces: 1.16 +/- 0.72

Urine: 0.60 +/- 0.11

Cage wash: 0.29 +/- 0.10

Total: 12.0 +/- 3.29

% of recovered dose (mean +/- S.E.M.) N = 6

Bile: 85.6 +/- 2.97

Faeces: 5.96 +/- 3.41

Urine: 5.74 +/- 0.91

Cage wash: 2.73 +/- 0.92

Total: 100